Brain tumors are the most common group of solid malignancies in children, causing devastating mortality and morbidity in an understudied patient population. The goal of this program project is to improve understanding and treatment of pediatric high-grade glioma and medulloblastoma. During the last funding period, Project Leaders worked together to develop novel mouse models that provided key biological insights into normal and tumorigenic growth in the brain, used these models for preclinical testing of new therapeutic agents, and translated research results into clinical trials. Whole genome sequencing efforts also provided an unprecedented view of the genomic landscape of pediatric high-grade glioma and medulloblastoma, including newly identified recurrent mutations, some of which impact epigenetic regulation. The current proposal builds on these exciting findings, with four highly interactive projects that plan state-of-the-art approaches to determine the mechanisms through which genetic and epigenetic alterations drive tumorigenesis in the developing brain. An Administrative Core, a Bioinformatics Core, and a Neuropathology Core provide essential support to all projects. In Project 1, S Baker will investigate connections between neural development, gliomagenesis and epigenetic regulation, with a focus on recurrent histone H3 mutations found in pediatric high-grade glioma. In Project 2, P McKinnon will employ new mouse models of glioma to define critical connections between the DNA damage response in neural progenitors, replication stress, and tumorigenesis. In Project 3, M Roussel will extend her progress in developing a mouse model for the Group 3 subgroup of medulloblastoma to determine the connections between epigenetic regulation and MYC signaling in medulloblastoma tumorigenesis, and to identify small molecules targeting epigenetic modifiers that inhibit Group 3 medulloblastoma. In Project 4, R Gilbertson will build upon his success in defining and modeling medulloblastoma subtypes to determine the role of specific mutations in hindbrain development and medulloblastoma, and to develop and test subtype-specific therapies in preclinical models.